GAS SUPPLY, DEMAND AND MIDDLE EAR GAS BALANCE From the results of studies in monkeys, we developed a multi-level, interactive, feedback model to describe the efficiency of middle ear (ME) pressure-regulation and the pathophysiological consequences of disregulation. That model requires knowledge only of system geometry and the physiochemical properties of represented gases and tissues to predict the behavior of ME pressure and the conditions that favor transitions between normal and pathological states. If valid, the model allows for testing previously suggested mechanisms of ME pressure-regulation, defining the causal sequences leading to ME pressure disregulation (MEPD)/otitis media with effusion (OME) and identifying mediational links that could be targeted by treatments to prevent or "cure" MEPD related disease expressions. That model has not been calibrated to the specifications of the human ME nor have any of its specific predictions been tested for applicability to clinical disease. The experiments included in this translational research project develop an empirical database for testing the predictions of the model at the levels of individual components and when fully assembled. Specifically, we will characterize the properties of gas exchange across the three main pathways that affect ME pressure, i.e. passive exchange across the tympanic membrane (TM) and middle ear mucosa (MEM), and active/passive exchange across the Eustachian tube (ET). Because protocols for testing ET function (ETF) in humans are generally limited to ears with a nonintact TM, we plan to expand existing tests and to develop new protocols for testing ears with an intact TM in the controlled environment of a pressure-chamber. Also, we will evaluate four hypotheses relevant to our description of MEPD mediated OM expression during a viral upper-respiratory tract infection (vURI);i.e. 1) constitutional ETF defines the risk of otological complications during a vURI;2) transMEM inert gas exchange is increased by local, neurogenic inflammation;3) MEM inflammation, edema and effusion develop at a specific critical ME underpressure of approximately -200 mmH2O, and 4) transMEM inert gas exchange is increased by MEM inflammation.